Panic Disorder (PD) is a common psychiatric illness that afflicts approximately 6 million people annually in the US. Despite considerable research, the neurobiological basis of PD is poorly understood. Neurobiological models of panic propose a dysfunction in central metabolically driven alarm system coupled with a supersensitive fear/anxiety system. Although an underlying metabolic deficit has been proposed for PD it is currently unclear what metabolic triggers may initiate panic attacks in vulnerable individuals. Recently, elevated acidosis was hypothesized to be a major factor in induction of panic. This is supported by observations of acid-base dysbalance in PD. Panic attacks are often provoked by challenges causing pH imbalance. However, it is not well understood how metabolic disturbances in pH may translate to panic and fear responses. This association is critical to the pathophysiology of panicogenesis and may lead to more specific and effective therapies for PD. We recently cloned acid-sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) from rodent brain. TDAG8 is predominant in circumventricular organs (CVOs); recently identified as sensor sites for panic stimuli. Importantly, panic-associated responses are attenuated in TDAG8-deficient mice. TDAG8 acid-sensing may provide a core mechanism to explain the basis of panic attacks. The objective of this proposal is to delineate the mechanistic link between acid-sensing TDAG8 receptor and panic-relevant responses. Relevance of acid-sensing by TDAG8 in panic and fear responses will be tested under three specific aims. Aim 1 To determine the necessity of TDAG8 in the expression of fear, anxiety, cardiovascular and respiratory responses evoked by panicogens. Aim 2 To determine the regulation of cellular acid-sensing chemosensory responses in the CVOs by TDAG8. Aim 3 To determine the sufficiency of local TDAG8 activation by acidosis in the CVOs for inducing panic-like responses. Relevance: The TDAG8 receptor may provide important leads into how metabolic disturbances in pH get translated into panic responses. This association is critical to the pathophysiology of panic and may lead to more specific and effective therapies for PD. PUBLIC HEALTH RELEVANCE: Panic Disorder (PD) is a common and complex anxiety disorder with a life time prevalence of up to 4%. Specific treatments for PD are not available due to a poor understanding of how panic attacks are induced in panic-prone individuals. This R01 application proposes to investigate the link between acid-sensing and panic to explain how panic attacks can be triggered. Our studies will lead to an understanding of PD and provide novel treatments.